Use of a thienotriazolodiazephine to increase apolipoprotein A-I levels

ABSTRACT

9-methyl-4-phenyl-6H-thieno 3,2-f!-s-triazolo 4,3-a! 1,4!diazepine for the treatment and prevention of illnesses which are caused by low plasma apolipoprotein A-I levels as coronary coronary disease.

This application is a 371 of PCT/EP96/03814 filed Aug. 30, 1994.

The invention is based on the finding of novel physiological propertiesof the compound 9-methyl-4-phenyl-6H-thieno 3,2-f!-s-triazolo 4,3-a!1,4!-diazepine, hereinafter Compound C.

Compound C and its preparation are described in U.S. Pat. No. 4,155,913.This patent also describes analogs of Compound C and contains datashowing the anticonvulsant and muscle relaxant activity of one of theseanalogs.

It has now been found that Compound C is active in increasing plasmaapolipoprotein A-I (apo A-I). Apo A-I is a major protein constituent ofplasma high density lipoproteins (HDL). Low plasma levels of HDL areknown to be associated with an increased incidence of coronary arterydisease (CAD). The same applies to both low plasma levels of apo A-I andhigh levels of apolipoprotein B (apo B); J. of Biol. Chem. 264:6488-6494, 1989; Mayo Clin. Proc. 61: 313-320, 1986; New England J. ofMedicine 325: 373-381, 1991; Am. J. Cardiol. 69: 1015-1021, 1992; J. Am.College Cardiol. 19: 792-802, 1992.

In one aspect, the present invention relates to the use of Compound Cfor the manufacture of medicaments for the treatment and prevention ofillnesses which are caused by low plasma apo A-I levels. Examples ofsuch illnesses are the above mentioned CAD, mainly myocardialinfarction, and atherosclerosis.

In a further aspect the invention relates to plasma apo A-I levelsenhancing medicaments which contain Compound C as the active ingredient,as well as to a process for the manufacture of such medicaments, whichprocess comprises bringing Compound C and, if desired, one or more othertherapeutically valuable substances into a galenical administrationform.

In an other aspect the invention relates to a method of increasingplasma apo A-I levels in mammals, particularly human beings, whichmethod comprises administering an effective amount of Compound C.

The activity of Compound C on plasma levels of apo A-I can bedemonstrated by standard methods. For example, male hamsters were fed acoco-nut enriched diet. Ten controls and five drug treated animals wereused. Compound C was given mixed with the food at a daily dose of 30mg/kg for 10 days. The experiment was conducted as described in J. LipidRes. 36: 1567-1585, 1995. For each of the plasma parameters apo A-I, apoB and triglycerides, the mean concentrations in g/L or mg/dl at bothday-1 and day 10 of the assay are as follows:

    ______________________________________                                        Plasma Control:             Compound C:                                       parameter:                                                                           day-1     day 10     day-1   day 10                                    ______________________________________                                        apo A-I                                                                              1.00 ± 0.08                                                                          0.97 ± 0,09                                                                           0.91 ± 0.08                                                                        1.30 ± 0.15*                           (g/L)                                                                         apo B  0.79 ± 0.09                                                                          1.20 ±  0.84 ± 0.11                                                                        1.20 ± 0.35*                           (g/L)            0.19*                                                        triglycer-                                                                           312 ± 46                                                                              288 ± 34**                                                                           197 ± 23                                                                           307 ± 19**                             ides                                                                          (mg/dl)                                                                       ______________________________________                                         *significantly different (p < 0.05 paired ttest) as compared to day1          **not significantly different as compared to day1                        

The results show that the administration of Compound C results in anincrease over the control group of the apo A-I level withoutsignificantly affecting the apo B and triglycerides levels.

The administration of Compound C did not induce any manifest adverseeffect. The animals remained healthy, lively, kept eating and growing atnormal rates and were not showing any signs of sedation.

Compound C can be used as active ingredient in pharmaceuticalpreparations. The pharmaceutical preparations are administered orally,e.g. in the form of tablets, coated tablets, dragees, hard and softgelatine capsules, solutions, emulsions or suspensions. The activeingredient can be mixed with pharmaceutically inert, inorganic ororganic carriers in order to manufacture such preparations. Lactose,corn starch, talc, stearic acid or its salts can be used, for example,as carriers for tablets, coated tablets, dragees and hard gelatinecapsules. Suitable carriers for soft gelatine capsules are, for example,vegetable oils, waxes or fats; depending on the nature of the activeingredient no carriers are, however, usually required in the case ofsoft gelatine capsules. Suitable carriers for the manufacture ofsolutions and syrups are, for examples, water, saccharose, invert sugarand glucose. The pharmaceutical preparations can also containpreservatives, solubilizers, stabilizers, wetting agents, emulsifiers,sweeteners, colorants, flavorants, salts for varying the osmoticpressure, buffers, coating agents or antioxidants. They can also containother therapeutically valuable substances.

As mentioned earlier, Compound C can be used in the control orprevention of illnesses such as atherosclerosis and CAD, particularlymyocardial infarction. The dosage can vary within wide limits and will,of course, be fitted to the individual requirements in each particularcase. In general, an oral daily dosage of about 10 mg to about 1 g,preferably of about 100 to about 500 mg, should be sufficient. The dailydosage can be taken in one, two or three single doses, e.g. with food. Asingle dosage form contains from about 10 to 500 mg of Compound C.

A hard gelatine capsule contains e.g. 30, 60, 125, 250 or 500 mg ofCompound C and finely crystalline lactose to a final fill weight of580-590 mg.

I claim:
 1. A method for preventing coronary artery disease whichcomprises administering an effective amount of the compound9-methyl-4-phenyl-6H-thieno 3,2-f!-s-triazolo 4,3-a! 1,4!diazepine to anindividual not afflicted with coronary artery disease.
 2. The method ofclaim 1, wherein the coronary artery disease is atherosclerosis.
 3. Themethod of claim 1, wherein the coronary artery disease is myocardialinfarction.
 4. The method of claim 1, wherein the administeringcomprises orally delivering a daily dosage of9-methyl-4-phenyl-6H-thieno 3,2-f!-s-triazolo 4,3-a! 1,4!diazepine in anamount from about 10 mg to about 1 g per day.
 5. The method of claim 4,wherein the administering comprises orally delivering a daily dosage of9-methyl-4-phenyl-6H-thieno 3,2-f!-s-triazolo 4,3-a! 1,4!diazepine in anamount from about 100 mg to about 500 mg per day.
 6. The method of claim4, wherein the administering is performed once a day.
 7. The method ofclaim 4, wherein the administering is performed twice a day.
 8. Themethod of claim 4, wherein the administering is performed three times aday.
 9. A method for treating coronary artery disease which comprisesadministering an effective amount of the compound9-methyl-4-phenyl-6H-thieno 3,2-f!-s-triazolo 4,3-a! 1,4!diazepine to anindividual afflicted with coronary artery disease.
 10. The method ofclaim 9, wherein the coronary artery disease is atherosclerosis.
 11. Themethod of claim 9, wherein the coronary artery disease is myocardialinfarction.
 12. The method of claim 9, wherein the administeringcomprises orally delivering a daily dosage of9-methyl-4-phenyl-6H-thieno 3,2-f!-s-triazolo 4,3-a! 1,4!diazepine in anamount from about 10 mg to about 1 g per day.
 13. The method of claim12, wherein the administering comprises orally delivering a daily dosageof 9-methyl-4-phenyl-6H-thieno 3,2-f!-s-triazolo 4,3-a! 1,4!diazepine inan amount from about 100 mg to about 500 mg per day.
 14. The method ofclaim 12, wherein the administering is performed once a day.
 15. Themethod of claim 12, wherein the administering is performed twice a day.16. The method of claim 12, wherein the administering is performed threetimes a day.